Alzheimer's disease (AD) is the most common and severe age-associated neurodegenerative dementia. Because of an aging population, it is estimated that 15 million individuals will be affected by AD by the year. 2050, with a direct healt care cost far exceeding $1 trillion. There is currently no cure for AD, and the need to develop innovative, effective treatment targets is urgent. Notably, rare individuals remain cognitively intact despite the presence of neuropathological features usually associated with a fully symptomatic stage of AD. The existence of these unusual cases, herein referred to as Non-Demented with Alzheimer's disease Neuropathology (NDAN), suggests that there is a natural way for the human brain to resist (or significantly delay) the neurotoxic events that normally lead to cognitive impairment in AD. It follows that understanding the cellular mechanisms involved in such extraordinary resistance would reveal a very effective therapeutic target. A growing body of evidence and our own preliminary data show that the number of neural progenitor cells in the hippocampus (an area of the brain that plays a critical role in learning and memory and is most affected by AD) is significantly reduced in the brains of AD patients, while it is increased in brains of NDAN individuals. In this proposal, we will test the hypothesis that the generation and integration of new neurons in the hippocampus is a key protective feature of the newly appreciated intrinsic ability of the human brain to resist the development of AD-associated cognitive decline. In Specific Aim 1 we will test the sub-hypothesis that normal generation and integration of progenitor cell-derived new neurons accompany intact cognitive function in NDAN individuals. In Specific Aim 2 we will test the sub-hypothesis that the epigenetic regulation of proliferation and differentiation of hippocampal neural progenitor cells differ between AD patients and NAND individuals. These studies will be performed on autopsied brain tissue provided to us as part of an ongoing collaboration with Dr. Randy Woltjer, Director of the pathology core of the Layton AD Center at Oregon Health Science University, Portland, OR. At the completion of the work proposed, we will have characterized the process of neurogenesis in NDAN subjects as compared to AD individuals, with the overall objective of demonstrating the existence of a significant relationship between intact/increased neurogenesis and preserved cognitive competency despite the presence of AD neuropathology. Furthermore, we will be able to generate a specific working hypothesis on the mechanisms underlying the observed cognitive resistance of NDAN individuals based on specific pathways involved in the process of neurogenesis. This is the first fundamental step toward achieving our goal of understanding the molecular mechanisms of cognitive resistance in NDAN individuals, which will ultimately allow us to identify an effective target for prevention and/or treatment of cognitive decline in AD.